bims-medebr 2023-08-06 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–08–06
twenty papers selected by
Regina F. Fernández, Johns Hopkins University

Progressive myoclonic epilepsy type 1 (EPM1) patients present with abnormal 1H MRS brain metabolic profiles associated with cognitive function.
An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.
The effects of general anesthetics on mitochondrial structure and function in the developing brain.
Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.
Glycine disrupts myelin, glutamatergic neurotransmission, and redox homeostasis in a neonatal model for non ketotic hyperglycinemia.
The expanding organelle lipidomes: current knowledge and challenges.
Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.
Single subanesthetic dose of ketamine produces delayed impact on brain [18F]FDG PET imaging and metabolic connectivity in rats.
Roadmap for Postnatal Brain Maturation: Changes in Gray and White Matter Composition during Development Measured by Fourier Transformed Infrared Microspectroscopy.
CETP inhibitor evacetrapib enters mouse brain tissue.
The synaptic vesicle protein Mover/TPRG1L is associated with lipid droplets in astrocytes.
Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).
Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target.
Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.
Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic features.
The Role of Mitochondrial Biogenesis in Ischemic Stroke.
Differential effects of social isolation on oligodendrocyte development in different brain regions: insights from a canine model.
Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
Inter-tissue communication of mitochondrial stress and metabolic health.
Tracking the Metabolic Fate of Exogenous Arachidonic Acid in Ferroptosis Using Dual-Isotope Labeling Lipidomics.

Neuroimage Clin. 2023 Jul 03. pii: S2213-1582(23)00148-1. [Epub ahead of print]39 103459

Progressive myoclonic epilepsy type 1 (EPM1) patients present with abnormal 1H MRS brain metabolic profiles associated with cognitive function.

Jelena Hyppönen, Vili Paanila, Marja Äikiä, Päivi Koskenkorva, Mervi Könönen, Ritva Vanninen, Esa Mervaala, Reetta Kälviäinen, Juhana Hakumäki.

   PURPOSE: Progressive myoclonic epilepsy, type 1A (EPM1, Unverricht-Lundborg disease), is a rare neurodegenerative autosomal recessive disorder characterized by stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. Patients develop neurological symptoms, including ataxia, intention tremor, and dysarthria, over time, with relatively limited and nonspecific MRI atrophy findings. The effects of the disease on brain metabolism are largely unknown.
METHOD: Eighteen EPM1 patients (9 M, 9F) underwent clinical evaluation and neuropsychological testing, which included the assessment of intellectual ability, verbal memory, and psychomotor and executive functions. Magnetic resonance spectroscopy (MRS) and imaging (MRI) were performed on a 1.5 T MRI system. 2D MRS chemical shift imaging (CSI) maps (TE = 270) were obtained from the following regions of the brain: basal ganglia, thalamus, insula, splenium, and occipital white and gray matter, and N-acetyl-aspartate (NAA)-, choline (Cho)-, and lactate (Lac)-to-creatine (Cr) ratios were analyzed. Ten healthy age-and sex-matched subjects (5M, 5F) were used as controls for MRS.
RESULTS: We found significant brain metabolic changes involving lactate, NAA, and choline, which are widespread in the basal ganglia, thalamic nuclei, insula, and occipital areas of EPM1 patients. Changes, especially in the right insula, basal ganglia, and thalamus, were associated with intellectual abilities and impairment of the psychomotor and executive functions of EPM1 patients.
CONCLUSION: Multiple brain metabolic alterations suggest the presence of neurodegeneration associated with EPM1 progression. The changes in metabolite ratios are associated with the neurocognitive dysfunction caused by the disease. However, the role of MRS findings in understanding pathophysiology of EPM1 warrants further studies.

Keywords:  Brain; Cognition; EPM1; MRS; Neuropsychology; Spectroscopy

DOI:  https://doi.org/10.1016/j.nicl.2023.103459
Commun Biol. 2023 07 29. 6(1): 789

An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.

Karo Talvio, Victoria A Wagner, Rimante Minkeviciene, Jay S Kirkwood, Anna O Kulinich, Juzoh Umemori, Anil Bhatia, Manhoi Hur, Reijo Käkelä, Iryna M Ethell, Maija L Castrén.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.

DOI: https://doi.org/10.1038/s42003-023-05147-9
Front Neurol. 2023 ;14 1179823

The effects of general anesthetics on mitochondrial structure and function in the developing brain.

Kaley Hogarth, Doorsa Tarazi, Jason T Maynes.

  The use of general anesthetics in modern clinical practice is commonly regarded as safe for healthy individuals, but exposures at the extreme ends of the age spectrum have been linked to chronic cognitive impairments and persistent functional and structural alterations to the nervous system. The accumulation of evidence at both the epidemiological and experimental level prompted the addition of a warning label to inhaled anesthetics by the Food and Drug Administration cautioning their use in children under 3 years of age. Though the mechanism by which anesthetics may induce these detrimental changes remains to be fully elucidated, increasing evidence implicates mitochondria as a potential primary target of anesthetic damage, meditating many of the associated neurotoxic effects. Along with their commonly cited role in energy production via oxidative phosphorylation, mitochondria also play a central role in other critical cellular processes including calcium buffering, cell death pathways, and metabolite synthesis. In addition to meeting their immense energy demands, neurons are particularly dependent on the proper function and spatial organization of mitochondria to mediate specialized functions including neurotransmitter trafficking and release. Mitochondrial dependence is further highlighted in the developing brain, requiring spatiotemporally complex and metabolically expensive processes such as neurogenesis, synaptogenesis, and synaptic pruning, making the consequence of functional alterations potentially impactful. To this end, we explore and summarize the current mechanistic understanding of the effects of anesthetic exposure on mitochondria in the developing nervous system. We will specifically focus on the impact of anesthetic agents on mitochondrial dynamics, apoptosis, bioenergetics, stress pathways, and redox homeostasis. In addition, we will highlight critical knowledge gaps, pertinent challenges, and potential therapeutic targets warranting future exploration to guide mechanistic and outcomes research.

Keywords:  anesthesia; developing brain; mitochondria; mitochondrial dysfunction; neurotoxicity

DOI:  https://doi.org/10.3389/fneur.2023.1179823
Cell Death Dis. 2023 Aug 03. 14(8): 496

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Volha Liaudanskaya, Nicholas J Fiore, Yang Zhang, Yuka Milton, Marilyn F Kelly, Marly Coe, Ariana Barreiro, Victoria K Rose, Matthew R Shapiro, Adam S Mullis, Anna Shevzov-Zebrun, Mathew Blurton-Jones, Michael J Whalen, Aviva J Symes, Irene Georgakoudi, Thomas J F Nieland, David L Kaplan.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

DOI: https://doi.org/10.1038/s41419-023-05980-0
Biochimie. 2023 Aug 02. pii: S0300-9084(23)00183-9. [Epub ahead of print]

Glycine disrupts myelin, glutamatergic neurotransmission, and redox homeostasis in a neonatal model for non ketotic hyperglycinemia.

Belisa Parmeggiani, Marian Flores Signori, Cristiane Cecatto, Marina Rocha Frusciante, Manuela Bianchin Marcuzzo, Débora Guerini Souza, Rafael Teixeira Ribeiro, Bianca Seminotti, Diogo Onofre Gomes de Souza, César Augusto João Ribeiro, Moacir Wajner, Guilhian Leipnitz.

  Non ketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by mutations in the genes encoding glycine cleavage system proteins. Classic NKH has a neonatal onset, and patients present with severe neurodegeneration. Although glycine accumulation has been implicated in NKH pathophysiology, the exact mechanisms underlying the neurological damage and white matter alterations remain unclear. We investigated the effects of glycine in the brain of neonatal rats and MO3.13 oligodendroglial cells. Glycine decreased myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in the corpus callosum and striatum of rats on post-natal day (PND) 15. Glycine also reduced neuroglycan 2 (NG2) and N-methyl-d-aspartate receptor subunit 1 (NR1) in the cerebral cortex and striatum on PND15. Moreover, glycine reduced striatal glutamate aspartate transporter 1 (GLAST) content and neuronal nucleus (NeuN), and increased glial fibrillary acidic protein (GFAP) on PND15. Glycine also increased DCFH oxidation and malondialdehyde levels and decreased GSH concentrations in the cerebral cortex and striatum on PND6, but not on PND15. Glycine further reduced viability but did not alter DCFH oxidation and GSH levels in MO3.13 cells after 48- and 72-h incubation. These data indicate that impairment of myelin structure and glutamatergic system and induction of oxidative stress are involved in the neuropathophysiology of NKH.

Keywords:  Brain; Glutamatergic system; Glycine; Myelin; Non ketotic hyperglycinemia

DOI:  https://doi.org/10.1016/j.biochi.2023.07.022
Cell Mol Life Sci. 2023 Aug 02. 80(8): 237

The expanding organelle lipidomes: current knowledge and challenges.

Maria J Sarmento, Alicia Llorente, Toni Petan, Denis Khnykin, Iuliana Popa, Matea Nikolac Perkovic, Marcela Konjevod, Morana Jaganjac.

  Lipids in cell membranes and subcellular compartments play essential roles in numerous cellular processes, such as energy production, cell signaling and inflammation. A specific organelle lipidome is characterized by lipid synthesis and metabolism, intracellular trafficking, and lipid homeostasis in the organelle. Over the years, considerable effort has been directed to the identification of the lipid fingerprints of cellular organelles. However, these fingerprints are not fully characterized due to the large variety and structural complexity of lipids and the great variability in the abundance of different lipid species. The process becomes even more challenging when considering that the lipidome differs in health and disease contexts. This review summarizes the information available on the lipid composition of mammalian cell organelles, particularly the lipidome of the nucleus, mitochondrion, endoplasmic reticulum, Golgi apparatus, plasma membrane and organelles in the endocytic pathway. The lipid compositions of extracellular vesicles and lamellar bodies are also described. In addition, several examples of subcellular lipidome dynamics under physiological and pathological conditions are presented. Finally, challenges in mapping organelle lipidomes are discussed.

Keywords:  Cellular organelles; Lipidomics; Lipids; Mass spectrometry; Subcellular fractionation

DOI:  https://doi.org/10.1007/s00018-023-04889-3
Mol Psychiatry. 2023 Aug 01.

Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.

Mohammed H Sarikahya, Samantha L Cousineau, Marta De Felice, Hanna J Szkudlarek, Karen K W Wong, Marieka V DeVuono, Kendrick Lee, Mar Rodríguez-Ruiz, Dana Gummerson, Emma Proud, Tsun Hay Jason Ng, Roger Hudson, Tony Jung, Daniel B Hardy, Ken K-C Yeung, Susanne Schmid, Walter Rushlow, Steven R Laviolette.

With increasing maternal cannabis use, there is a need to investigate the lasting impact of prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis, on cognitive/memory function. The endocannabinoid system (ECS), which relies on polyunsaturated fatty acids (PUFAs) to function, plays a crucial role in regulating prefrontal cortical (PFC) and hippocampal network-dependent behaviors essential for cognition and memory. Using a rodent model of prenatal cannabis exposure (PCE), we report that male and female offspring display long-term deficits in various cognitive domains. However, these phenotypes were associated with highly divergent, sex-dependent mechanisms. Electrophysiological recordings revealed hyperactive PFC pyramidal neuron activity in both males and females, but hypoactivity in the ventral hippocampus (vHIPP) in males, and hyperactivity in females. Further, cortical oscillatory activity states of theta, alpha, delta, beta, and gamma bandwidths were strongly sex divergent. Moreover, protein expression analyses at postnatal day (PD)21 and PD120 revealed primarily PD120 disturbances in dopamine D1R/D2 receptors, NMDA receptor 2B, synaptophysin, gephyrin, GAD67, and PPARα selectively in the PFC and vHIPP, in both regions in males, but only the vHIPP in females. Lastly, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we identified region-, age-, and sex-specific deficiencies in specific neural PUFAs, namely docosahexaenoic acid (DHA) and arachidonic acid (ARA), and related metabolites, in the PFC and hippocampus (ventral/dorsal subiculum, and CA1 regions). This study highlights several novel, long-term and sex-specific consequences of PCE on PFC-hippocampal circuit dysfunction and the potential role of specific PUFA signaling abnormalities underlying these pathological outcomes.

DOI: https://doi.org/10.1038/s41380-023-02190-0
Front Neurosci. 2023 ;17 1213941

Single subanesthetic dose of ketamine produces delayed impact on brain [18F]FDG PET imaging and metabolic connectivity in rats.

Sarah Chaib, Caroline Bouillot, Sandrine Bouvard, Benjamin Vidal, Luc Zimmer, Elise Levigoureux.

   Introduction: Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact.
Methods: We explored the glucose metabolism with [18F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [18F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs.
Results: No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline.
Discussion: This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.

Keywords:  FDG; PET; ketamine; metabolic connectivity; neuroimaging

DOI:  https://doi.org/10.3389/fnins.2023.1213941
ACS Chem Neurosci. 2023 Aug 04.

Roadmap for Postnatal Brain Maturation: Changes in Gray and White Matter Composition during Development Measured by Fourier Transformed Infrared Microspectroscopy.

Marta Peris, Núria Benseny-Cases, Gemma Manich, Oriana Zerpa, Beatriz Almolda, Àlex Perálvarez-Marín, Berta González, Bernardo Castellano.

  Key events in postnatal brain development, such as neuronal migration, synaptogenesis, and myelination, shape the adult brain. These events are reflected in changes in gray and white matter (GM and WM) occurring during this period. Therefore, precise knowledge of GM and WM composition in perinatal brain development is crucial to characterizing brain formation as well as the neurodevelopmental disruption observed in diseases such as autism and schizophrenia. In this study, we combined histochemical and immunohistochemical staining with biochemical and biophysical analyses using Fourier transform infrared (IR) microspectroscopy (μFTIR) to better understand the chemical changes during postnatal developmental myelination. For this purpose, we analyzed the GM and WM in the mouse brain and cerebellum (strain C57BL/6) from postnatal day 0 (P0) to day P28 and established presumed correlations between staining and IR data. IR spectra allowed the (i) quantification of lipid and protein content through the CH2/amide I ratio, (ii) determination of chemical characteristics of lipids, such as the presence of unsaturated bonds in the carbonate chain or carbonyls from ester groups in the polar head, and (iii) determination of the protein secondary structure (α-helix and intramolecular β-sheets). The results indicate that the increase in the CH2/amide I ratio calculated from the μFTIR data correlates well with lipid histochemical staining. IR data indicated a change in the lipid composition in WM since carbonyl and unsaturated olefinic groups do not increase when lipids accumulate during myelination. Our correlation analysis between IR data and immunohistochemical staining of myelin-associated proteins revealed that myelin oligodendrocyte protein correlated well with lipid accumulation, while myelin basic protein appeared before lipid modifications, which indicated that myelin-associated proteins and lipid deposition were not synchronic. These events were related to a decrease in the intramolecular β/α protein ratio. Our results indicate that lipids and proteins in WM substantially change their composition due to primary myelination, and according to results obtained from staining, these modifications are better described by lipid histochemical staining than by immunohistochemistry against myelin-related proteins. In conclusion, μFTIR can be a useful technique to study WM during perinatal development and provide detailed information about alterations in the chemical composition related to neurodevelopmental diseases.

Keywords:  development; gray matter; myelination; white matter; μFTIR

DOI:  https://doi.org/10.1021/acschemneuro.3c00237
Front Pharmacol. 2023 ;14 1171937

CETP inhibitor evacetrapib enters mouse brain tissue.

Jasmine Phénix, Jonathan Côté, Denis Dieme, Sherilyn J Recinto, Felix Oestereich, Sasen Efrem, Sami Haddad, Michèle Bouchard, Lisa Marie Munter.

  High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease.

Keywords:  Alzheimer’s disease; PBPK model; brain; cholesterol; cholesteryl ester transfer protein (CETP); evacetrapib; inhibitor; pharmacokinetic

DOI:  https://doi.org/10.3389/fphar.2023.1171937
Glia. 2023 Aug 04.

The synaptic vesicle protein Mover/TPRG1L is associated with lipid droplets in astrocytes.

Jeremy Krohn, Florelle Domart, Thanh Thao Do, Thomas Dresbach.

  Crucial brain functions such as neurotransmission, myelination, and signaling pose a high demand for lipids. Lipid dysregulation is associated with neuroinflammation and neurodegeneration. Astrocytes protect neurons from lipid induced damage by accumulating and metabolizing toxic lipids in organelles called lipid droplets (LDs). LDs have long been considered as lipid storage compartments in adipocytes, but less is known about their biogenesis and composition in the brain. In particular, proteins covering the LD surface are not yet fully identified. Here, we report that the presynaptic protein Mover/TPRG1L, which regulates the probability of neurotransmitter release in neurons, is a component of the LD coat in astrocytes. Using conventional and super-resolution microscopy, we demonstrate that Mover surrounds naive and oleic acid induced astrocytic LDs. We confirm the identity of astrocytic LDs using the neutral lipid stains Bodipy and LipidTox, as well as immunofluorescence for perilipin-2, a known component of the LD coat. In astrocytes, recombinant Mover was sufficient to induce an accumulation of LDs. Furthermore, we identified point mutations that abolish targeting to LDs and show similarities in the required binding sequences for association to the presynapse and LDs. Our results show that Mover is not only a presynaptic protein but also a candidate for LD regulation. This highlights the dual role of Mover in synaptic transmission and regulation of astrocytic LDs, which may be particularly important in the context of lipid-related neurological disorders.

Keywords:  Mover; TPRG1L; astrocytes; lipid droplets; oleic acid; super-resolution microscopy

DOI:  https://doi.org/10.1002/glia.24452
Mol Neurobiol. 2023 Jul 31.

Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).

Dhivya Venkatesan, Mahalaxmi Iyer, Arul Narayanasamy, Abilash Valsala Gopalakrishnan, Balachandar Vellingiri.

  Parkinson's disease (PD) is an advancing age-associated progressive brain disorder which has various diverse factors, among them mitochondrial dysfunction involves in dopaminergic (DA) degeneration. Aging causes a rise in mitochondrial abnormalities which leads to structural and functional modifications in neuronal activity and cell death in PD. This ends in deterioration of mitochondrial function, mitochondrial alterations, mitochondrial DNA copy number (mtDNA CN) and oxidative phosphorylation (OXPHOS) capacity. mtDNA levels or mtDNA CN in PD have reported that mtDNA depletion would be a predisposing factor in PD pathogenesis. To maintain the mtDNA levels, therapeutic approaches have been focused on mitochondrial biogenesis in PD. The depletion of mtDNA levels in PD can be influenced by autophagic dysregulation, apoptosis, neuroinflammation, oxidative stress, sirtuins, and calcium homeostasis. The current review describes the regulation of mtDNA levels and discusses the plausible molecular pathways in mtDNA CN depletion in PD pathogenesis. We conclude by suggesting further research on mtDNA depletion which might show a promising effect in predicting and diagnosing PD.

Keywords:  Copy number; Mitochondrial DNA; Molecular pathways; Parkinson’s disease; TFAM; Therapeutic strategies

DOI:  https://doi.org/10.1007/s12035-023-03500-x
Biochem Pharmacol. 2023 Jul 28. pii: S0006-2952(23)00308-8. [Epub ahead of print]215 115717

Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target.

Ya-Na Yang, Mao-Qing Zhang, Feng-Lin Yu, Bing Han, Ming-Yue Bao, Yan-He, Xing Li, Yuan Zhang.

  Neurodegenerative disorders (NDDs) are characterized by progressive loss of selectively vulnerable neuronal populations and myelin sheath, leading to behavioral and cognitive dysfunction that adversely affect the quality of life. Identifying novel therapies that attenuate the progression of NDDs would be of significance. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a widely expressed transcriptional regulator, modulates the expression of genes engaged in mitochondrial biosynthesis, metabolic regulation, and oxidative stress (OS). Emerging evidences point to the strong connection between PGC-1α and NDDs, suggesting its positive impaction on the progression of NDDs. Therefore, it is urgent to gain a deeper and broader understanding between PGC-1α and NDDs. To this end, this review presents a comprehensive overview of PGC-1α, including its basic characteristics, the post-translational modulations, as well as the interacting transcription factors. Secondly, the pathogenesis of PGC-1α in various NDDs, such as Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD) is briefly discussed. Additionally, this study summarizes the underlying mechanisms that PGC-1α is neuroprotective in NDDs via regulating neuroinflammation, OS, and mitochondrial dysfunction. Finally, we briefly outline the shortcomings of current NDDs drug therapy, and summarize the functions and potential applications of currently available PGC-1α modulators (activator or inhibitors). Generally, this review updates our insight of the important role of PGC-1α on the development of NDDs, and provides a promising therapeutic target/ drug for the treatment of NDDs.

Keywords:  Mitochondrial dysfunction; Neurodegenerative disorders; Neuroinflammation; Oxidative stress; Peroxisome proliferator-activated receptor γ coactivator-1α

DOI:  https://doi.org/10.1016/j.bcp.2023.115717
Cell Rep. 2023 Jul 29. pii: S2211-1247(23)00857-4. [Epub ahead of print]42(8): 112846

Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.

Anjaneyulu Murari, Shauna-Kay Rhooms, Divya Vimal, Kaniz Fatima Binte Hossain, Sanjay Saini, Maximino Villanueva, Michael Schlame, Edward Owusu-Ansah.

  Several phospholipid (PL) molecules are intertwined with some mitochondrial complex I (CI) subunits in the membrane domain of CI, but their function is unclear. We report that when the Drosophila melanogaster ortholog of the intramitochondrial PL transporter, STARD7, is severely disrupted, assembly of the oxidative phosphorylation (OXPHOS) system is impaired, and the biogenesis of several CI subcomplexes is hampered. However, intriguingly, a restrained knockdown of STARD7 impairs the incorporation of NDUFS5 and NDUFA1 into the proximal part of the CI membrane domain without directly affecting the incorporation of subunits in the distal part of the membrane domain, OXPHOS complexes already assembled, or mitochondrial cristae integrity. Importantly, the restrained knockdown of STARD7 appears to induce a modest amount of cardiolipin remodeling, indicating that there could be some alteration in the composition of the mitochondrial phospholipidome. We conclude that PLs can regulate CI biogenesis independent of their role in maintaining mitochondrial membrane integrity.

Keywords:  CP: Molecular biology; Drosophila; NDUFA1; NDUFS5; OXPHOS; STARD7; complex I; mitochondria; phospholipid

DOI:  https://doi.org/10.1016/j.celrep.2023.112846
Hum Mol Genet. 2023 Aug 02. pii: ddad124. [Epub ahead of print]

Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic features.

Zhigang Liu, Baozhong Xin, Iris N Smith, Valerie Sency, Julia Szekely, Anna Alkelai, Alan Shuldiner, Stephanie Efthymiou, Farrah Rajabi, Stephanie Coury, Catherine A Brownstein, Sabine Rudnik-Schöneborn, Ange-Line Bruel, Julien Thevenon, Shimriet Zeidler, Parul Jayakar, Axel Schmidt, Kirsten Cremer, Hartmut Engels, Sophia O Peters, Maha S Zaki, Ruizhi Duan, Changlian Zhu, Yiran Xu, Chao Gao, Tania Sepulveda-Morales, Reza Maroofian, Issam A Alkhawaja, Mariam Khawaja, Hunaida Alhalasah, Henry Houlden, Jill A Madden, Valentina Turchetti, Dana Marafi, Pankaj B Agrawal, Ulrich Schatz, Ari Rotenberg, Joshua Rotenberg, Grazia M S Mancini, Somayeh Bakhtiari, Michael Kruer, Isabelle Thiffault, Steffen Hirsch, Maja Hempel, Lara G Stühn, Tobias B Haack, Jennifer E Posey, James R Lupski, Hyunpil Lee, Nicholas B Sarn, Charis Eng, Claudia Gonzaga-Jauregui, Bin Zhang, Heng Wang.

  PPP1R3F (R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures, and other neurological findings including tone, gait, and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization, and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

Keywords:  PPP1R3F; X-linked; autism; developmental delay; glycogen metabolism; intellectual disability; protein phosphatase 1; seizure

DOI:  https://doi.org/10.1093/hmg/ddad124
J Integr Neurosci. 2023 Jul 05. 22(4): 88

The Role of Mitochondrial Biogenesis in Ischemic Stroke.

Behrouz Shademan, Cigir Biray Avci, Vahidreza Karamad, Gholamreza Jahangirzadeh Soureh, Jalhe Bagheri Hamzyan Olia, Farzaneh Esmaily, Alireza Nourazarian, Masoud Nikanfar.

  Ischaemic stroke is a sudden neurological disorder caused by localised cerebral ischaemia and persistent cerebral infarction. Occlusion of large arteries due to atherothrombosis, cerebral embolism (i.e., embolic infarction), no thrombotic occlusion in small, deep cerebral arteries (i.e., lacunar infarction), and stenosis of proximal arteries due to hypotension leading to decreased cerebral blood flow in arterial supply zones are the most common causes of ischemic stroke (i.e., hemodynamic stroke). It is now known that organelles play an important role in various signaling events and cellular functions. The molecular mechanisms of mitochondria are involved in cerebral ischemia by generating and scavenging reactive oxygen species, apoptosis, biogenesis, mitochondrial dynamics, and inflammation are all examples of electron transport chain dysfunction. More knowledge about the involvement of mitochondria in ischemia-induced neuronal death and neuronal protection will contribute to the development of better treatment programs for stroke syndromes such as ischemic stroke.

Keywords:  electron transport chain; ischemic stroke; mitochondrial biogenesis; neuronal death

DOI:  https://doi.org/10.31083/j.jin2204088
Front Cell Neurosci. 2023 ;17 1201295

Differential effects of social isolation on oligodendrocyte development in different brain regions: insights from a canine model.

Huilin Hong, Chao Guo, Xueru Liu, Liguang Yang, Wei Ren, Hui Zhao, Yuan Li, Zhongyin Zhou, Sin Man Lam, Jidong Mi, Zhentao Zuo, Cirong Liu, Guo-Dong Wang, Yan Zhuo, Ya-Ping Zhang, Yixue Li, Guanghou Shui, Yong Q Zhang, Ying Xiong.

  Social isolation (SI) exerts diverse adverse effects on brain structure and function in humans. To gain an insight into the mechanisms underlying these effects, we conducted a systematic analysis of multiple brain regions from socially isolated and group-housed dogs, whose brain and behavior are similar to humans. Our transcriptomic analysis revealed reduced expression of myelin-related genes specifically in the white matter of prefrontal cortex (PFC) after SI during the juvenile stage. Despite these gene expression changes, myelin fiber organization in PFC remained unchanged. Surprisingly, we observed more mature oligodendrocytes and thicker myelin bundles in the somatosensory parietal cortex in socially isolated dogs, which may be linked to an increased expression of ADORA2A, a gene known to promote oligodendrocyte maturation. Additionally, we found a reduced expression of blood-brain barrier (BBB) structural components Aquaporin-4, Occludin, and Claudin1 in both PFC and parietal cortices, indicating BBB disruption after SI. In agreement with BBB disruption, myelin-related sphingolipids were increased in cerebrospinal fluid in the socially isolated group. These unexpected findings show that SI induces distinct alterations in oligodendrocyte development and shared disruption in BBB integrity in different cortices, demonstrating the value of dogs as a complementary animal model to uncover molecular mechanisms underlying SI-induced brain dysfunction.

Keywords:  blood-brain barrier; dog; myelin; oligodendrocyte; parietal cortex; social isolation

DOI:  https://doi.org/10.3389/fncel.2023.1201295
EMBO Mol Med. 2023 Aug 03. e17399

Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.

Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling.

  Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.

Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin

DOI:  https://doi.org/10.15252/emmm.202317399
Life Metab. 2023 Feb;pii: load001. [Epub ahead of print]2(1):

Inter-tissue communication of mitochondrial stress and metabolic health.

Hanlin Zhang, Xinyu Li, Wudi Fan, Sentibel Pandovski, Ye Tian, Andrew Dillin.

  Mitochondria function as a hub of the cellular metabolic network. Mitochondrial stress is closely associated with aging and a variety of diseases, including neurodegeneration and cancer. Cells autonomously elicit specific stress responses to cope with mitochondrial stress to maintain mitochondrial homeostasis. Interestingly, mitochondrial stress responses may also be induced in a non-autonomous manner in cells or tissues that are not directly experiencing such stress. Such non-autonomous mitochondrial stress responses are mediated by secreted molecules called mitokines. Due to their significant translational potential in improving human metabolic health, there has been a surge in mitokine-focused research. In this review, we summarize the findings regarding inter-tissue communication of mitochondrial stress in animal models. In addition, we discuss the possibility of mitokine-mediated intercellular mitochondrial communication originating from bacterial quorum sensing.

Keywords:  inter-tissue communication; metabolic health; mitochondria; mitokine; quorum sensing

DOI:  https://doi.org/10.1093/lifemeta/load001
J Am Soc Mass Spectrom. 2023 Jul 31.

Tracking the Metabolic Fate of Exogenous Arachidonic Acid in Ferroptosis Using Dual-Isotope Labeling Lipidomics.

Noelle Reimers, Quynh Do, Rutan Zhang, Angela Guo, Ryan Ostrander, Alyson Shoji, Chau Vuong, Libin Xu.

Lipid metabolism is implicated in a variety of diseases, including cancer, cell death, and inflammation, but lipidomics has proven to be challenging due to the vast structural diversity over a narrow range of mass and polarity of lipids. Isotope labeling is often used in metabolomics studies to follow the metabolism of exogenously added labeled compounds because they can be differentiated from endogenous compounds by the mass shift associated with the label. The application of isotope labeling to lipidomics has also been explored as a method to track the metabolism of lipids in various disease states. However, it can be difficult to differentiate a single isotopically labeled lipid from the rest of the lipidome due to the variety of endogenous lipids present over the same mass range. Here we report the development of a dual-isotope deuterium labeling method to track the metabolic fate of exogenous polyunsaturated fatty acids, e.g., arachidonic acid, in the context of ferroptosis using hydrophilic interaction-ion mobility-mass spectrometry (HILIC-IM-MS). Ferroptosis is a type of cell death that is dependent on lipid peroxidation. The use of two isotope labels rather than one enables the identification of labeled species by a signature doublet peak in the resulting mass spectra. A Python-based software, D-Tracer, was developed to efficiently extract metabolites with dual-isotope labels. The labeled species were then identified with LiPydomics based on their retention times, collision cross section, and m/z values. Changes in exogenous AA incorporation in the absence and presence of a ferroptosis inducer were elucidated.

DOI: https://doi.org/10.1021/jasms.3c00181